The present disclosure generally relates to methods for treatment of disease-induced ataxia and non-ataxic imbalance. These symptoms can be treated in a patient by administering to the patient a compound having nicotinic acetylcholine receptor activity.
The role of nicotine on the human cerebellum is unclear. Nicotinic receptors appear responsible for disorders like Alzheimer's disease, anxiety, drug addition, epilepsy, Parkinson's Disease, schizophrenia, and Tourette's Syndrome. A report by Pereira et al. (NeuroReport 2001, 8, 1223-1226) showed that nicotine was associated with postural imbalance in non-smokers and occasionally in smokers, and also contributed to nystagmus and body sway (Spillane J D, Br. Med. J. 1955, 2: 1345, 1345-1351). Prenatal or neonatal nicotine exposure is thought to interfere with brain development in both human and animal studies. In fact, nicotine crosses the placenta (Al-Rejaie et al., Alcohol Clin. Exp. Res. 2006, 30(7), 1223-33). Smoking during pregnancy has been associated with miscarriage, sudden infant death syndrome (SIDS), and neurobehavioral disturbances including hyperactivity, depression, and anxiety (Smith et al., Brain Res. 2006, 1115(1), 16-25; Katz et al., J. Physiol. 1967, 138, 63-80). One study found that concurrent exposure of the human brain to alcohol and nicotine during a brain growth spurts reduced the total number of Purkinje cells (Arneric et al., Biochemical Pharmacology 2007, 74, 1092-1101). Another study compared the expression of nicotinic and muscarinic acetylcholine receptors in the first trimester in the pons, medulla oblongata, and cerebellum in 5-12 week gestation abortus of smoking and non-smoking women (Katz et al., J. Physiol. 1967, supra). The gene expression pattern of both α4 and α7 nicotinic receptor subunits in these regions was altered after smoking. These findings suggest that early prenatal nicotine exposure affects the normal developmental pattern of the human fetal cholinergic system.
Unlike nicotine, selective activation of nicotinic acetylcholine receptors, such as the α4β2 nicotinic acetylcholine receptor, may improve ataxia (Al-Rejaie et al., Alcohol Clin. Exp. Res. 2006, supra). Partial agonism of this receptor has been shown to decrease ataxia in animal models that was induced by alcohol (Al-Rejaie et al., Alcohol Clin. Exp. Res. 2006, supra) or tetrahydrocannabinoid (Smith et al., Brain Res. 2006, supra). Nicotinic acetylcholine receptors are rapidly desensitized by up-regulation (Katz et al., J. Physiol. 1967, supra), and partial α4β2 nicotinic acetylcholine receptors agonists like varenicline may paradoxically behave as antagonists rather than agonists (Arneric et al., Biochemical Pharmacology 2007, supra).
The α4β2 receptor in the mammalian brain has been linked to reward, tolerance and sensitization of nicotine (West et al., Psychopharmacology 2008; 197(3):371-7). In vivo studies of nicotinic acetylcholine receptors found an increased binding of [3H]nicotine in several areas of the brain in smokers, with prominent regional differences of distribution volumes in the cerebellum and brain stem, with an increased uptake in smokers compared to non-smokers (West et al., Psychopharmacology 2008, supra).
Varenicline is a recently-developed drug structurally based on cytisine, used as a prescription drug to combat smoking addition. Varenicline is a nicotinic receptor agonist, acting as a partial agonist of many nicotinic acetylcholine receptors, including the α4β2 subtype, found in the cerebellum (Schmitz-Hübsch et al., Neurology 2006, supra). Recent reports also show varenicline acts as a potent, full agonist of the α7 receptor subtype (K. Minalak, et al., Molec. Pharm., 70(3):801-805 (2006)). As noted above, nicotinic acetylcholine receptors rapidly desensitize by up-regulation of the active agent leading to the hypothesis that certain agents may act on these receptors functionally as antagonists, rather than as agonists.
Multiple neurodegenerative diseases and toxic exposures can lead to the progressive loss of the ability to coordinate movements. Symptoms of these physically devastating diseases and conditions include ataxia, imbalance, and sensory abnormalities. Ataxia and imbalance caused by, among other things, cerebellar disease, progressive supranuclear palsy (PSP) and atypical parkinonsims, currently have no treatment or cure.